title: Aluminum, copper, iron and zinc differentially alter amyloid-Aβ(1-42) aggregation and toxicity.
abstract: Amyloid-β(1-42) (Aβ) is believed to play a crucial role in the ethiopathogenesis of Alzheimer's Disease (AD). In particular, its interactions with biologically relevant metal ions may lead to the formation of highly neurotoxic complexes. Here we describe the species that are formed upon reacting Aβ with several biometals, namely copper, zinc, iron, and with non-physiological aluminum to assess whether different metal ions are able to differently drive Aβ aggregation. The nature of the resulting Aβ-metal complexes and of the respective aggregates was ascertained through a number of biophysical techniques, including electrospray ionization mass spectrometry, dynamic light scattering, fluorescence, transmission electron microscopy and by the use of conformation-sensitive antibodies (OC, αAPF). Metal binding to Aβ is shown to confer highly different chemical properties to the resulting complexes; accordingly, their overall aggregation behaviour was deeply modified. Both aluminum(III) and iron(III) ions were found to induce peculiar aggregation properties, ultimately leading to the formation of annular protofibrils and of fibrillar oligomers. Notably, only Aβ-aluminum was characterized by the presence of a relevant percentage of aggregates with a mean radius slightly smaller than 30 nm. In contrast, both zinc(II) and copper(II) ions completely prevented the formation of soluble fibrillary aggregates. The biological effects of the various Aβ-metal complexes were studied in neuroblastoma cell cultures: Aβ-aluminum turned out to be the only species capable of triggering amyloid precursor and tau181 protein overproduction. Our results point out that Al can effectively interact with Aβ, forming "structured" aggregates with peculiar biophysical properties which are associated with a high neurotoxicity.
authors.affiliation: Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314, USA.
authors.forename: Silvia
authors.initials: S
authors.lastname: Bolognin
authors.forename: Luigi
authors.initials: L
authors.lastname: Messori
authors.forename: Denise
authors.initials: D
authors.lastname: Drago
authors.forename: Chiara
authors.initials: C
authors.lastname: Gabbiani
authors.forename: Laura
authors.initials: L
authors.lastname: Cendron
authors.forename: Paolo
authors.initials: P
authors.lastname: Zatta
mesh_terms: D000535:Aluminum / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D000682:Amyloid / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D045744:Cell Line, Tumor; D003300:Copper / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007501:Iron / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013058:Mass Spectrometry; D046529:Microscopy, Electron, Transmission; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D020258:Neurotoxicity Syndromes / Q000378:metabolism* / Q000473:pathology; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D055503:Protein Multimerization / Q000187:drug effects; D015032:Zinc / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D003300:Copper; D000535:Aluminum; D007501:Iron; D015032:Zinc